The consolidation of long-term memory and the formation of long-term synaptic potentiation both require gene transcription and de novo protein synthesis. Multiple systems regulate these transcriptional events, offering several points of control over learning processes. Recent work from our lab and others has demonstrated a crucial role for epigenetic mechanisms in learning and plasticity, and this work has revealed links between disruption of epigenetic control and disorders of cognition. Inhibiting histone deacetylase (HDAC) enzymes enhances normal memory and rescue impairments of memory in mouse models of disease. Although this manipulation of the epigenetic regulation of transcription shows promise as a therapeutic tool, the underlying mechanisms of how it functions are unknown. Sin3a is a co-repressor protein that recruits HDAC enzymes to gene promoters to maintain their repression through histone hypoacetylation. The nuclear receptor subfamily 4 (Nr4a) transcription factors, regulated via histone acetylation by the cyclic AMP response element binding protein (CREB) and the co-activator CREB-binding protein (CBP), are also strong candidates for negative regulation by the Sin3a/HDAC complex. The Nr4a family of immediate early genes is transcribed immediately after neuronal activation, and the NR4A proteins are known to regulate the transcription of many genes important for memory and plasticity. I propose here to investigate in parallel the roles of Sin3a and the Nr4a transcription factors in hippocampal synaptic plasticity, and to uncover the identity of their regulatory targets in the hippocampal genome.

Public Health Relevance

Disruption of the machinery regulating plasticity, whether it is through a genetic disorder, neurodegenerative disease, or aging, impairs neuronal function and cognitive ability. Understanding the control of learning and memory through epigenetic pathways could offer novel therapeutic approaches to such disorders. Through the experiments proposed here, I hope to understand how hippocampal synaptic plasticity is regulated by epigenetic mechanisms, and how these pathways can be used to treat neuronal dysfunction. .